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25OHD is a partial agonist of TRPV1 whereby 25OHD can weakly activate TRPV1 yet antagonize the stimulatory effects of the full TRPV1 agonists capsaicin and oleoyl dopamine. 25OHD binds to TRPV1 within the same vanilloid binding pocket as capsaicin. 25OHD inhibits the potentiating effects of PKC-mediated TRPV1 activity. 25OHD reduces T-cell activation and trigeminal neuron calcium signalling mediated by TRPV1 activity. These results provide evidence that TRPV1 is a novel receptor for the biological actions of vitamin D in addition to the well-documented effects of vitamin D upon the nuclear vitamin D receptor. Our results may have important implications for our current understanding of certain diseases where TRPV1 and vitamin D deficiency have been implicated, such as chronic pain and autoimmune diseases, such as Type 1 Diabetes.
Learn More >Objectives Contemporary fear-avoidance models of chronic pain posit that fear of pain, and overgeneralization of fear to non-threatening stimuli is a potential pathway to chronic pain. While increasing experimental evidence supports this hypothesis, a comprehensive investigation requires testing in multiple modalities due to the diversity of symptomatology among individuals with chronic pain. In the present study we used an established tactile fear conditioning paradigm as an experimental model of allodynia and spontaneous pain fluctuations, to investigate whether stimulus generalization occurs resulting in fear of touch spreading to new locations. Methods In our paradigm, innocuous touch is presented either paired (predictable context) or unpaired (unpredictable context) with a painful electrocutaneous stimulus (pain-US). In the predictable context, vibrotactile stimulation to the index or little finger was paired with the pain-US (CS+), whilst stimulation of the other finger was never paired with pain (CS-). In the unpredictable context, vibrotactile stimulation to the index and little fingers of the opposite hand (CS1 and CS2) was unpaired with pain, but pain-USs occurred unpredictable during the intertrial interval. During the subsequent generalization phase, we tested the spreading of conditioned responses (self-reported fear of touch and pain expectancy) to the (middle and ring) fingers between the CS+ and CS-, and between the CS1 and CS2. Results Differential fear acquisition was evident in the predictable context from increased self-reported pain expectancy and self-reported fear for the CS + compared to the CS-. However, expectancy and fear ratings to the novel generalization stimuli (GS+ and GS-) were comparable to the responses elicited by the CS-. Participants reported equal levels of pain expectancy and fear to the CS1 and CS2 in the unpredictable context. However, the acquired fear did not spread in this context either: participants reported less pain expectancy and fear to the GS1 and GS2 than to the CS1 and CS2. As in our previous study, we did not observe differential acquisition in the startle responses. Conclusions Whilst our findings for the acquisition of fear of touch replicate the results from our previous study (Biggs et al., 2017), there was no evidence of fear generalization. We discuss the limitations of the present study, with a primary focus on procedural issues that were further investigated with post-hoc analyses, concluding that the present results do not show support for the hypothesis that stimulus generalization underlies spreading of fear of touch to new locations, and discuss how this may be the consequence of a context change that prevented transfer of acquisition.
Learn More >Migraine is a common, disabling neurological disorder with a genetic, environmental, and hormonal component with an annual prevalence estimated at ~15%. It is characterized by attacks of severe, usually unilateral and throbbing headache, and can be accompanied by nausea, vomiting, and photophobia. Migraine is clinically divided into two main subtypes: migraine with aura, when it is preceded by transient neurological disturbances due to cortical spreading depression (CSD), and migraine without aura. Activation and sensitization of trigeminal sensory neurons, leading to the release of pro-inflammatory peptides, is likely a key component in headache pain initiation and transmission in migraine. In the present review, we will focus on the function of two-pore-domain potassium (K) channels, which control trigeminal sensory neuron excitability and their potential interest for developing new drugs to treat migraine.
Learn More >Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.
Learn More >Hemispheric asymmetries within the brain have been identified across taxa and have been extensively studied since the early 19th century. Here, we discuss lateralization of a brain structure, the amygdala, and how this lateralization is reshaping how we understand the role of the amygdala in pain processing. The amygdala is an almond-shaped, bilateral brain structure located within the limbic system. Historically, the amygdala was known to have a role in the processing of emotions and attaching emotional valence to memories and other experiences. The amygdala has been extensively studied in fear conditioning and affect but recently has been shown to have an important role in processing noxious information and impacting pain. The amygdala is composed of multiple nuclei; of special interest is the central nucleus of the amygdala (CeA). The CeA receives direct nociceptive inputs from the parabrachial nucleus (PBN) through the spino-parabrachio-amygdaloid pathway as well as more highly processed cortical and thalamic input via the lateral and basolateral amygdala. Although the amygdala is a bilateral brain region, most data investigating the amygdala's role in pain have been generated from the right CeA, which has an overwhelmingly pro-nociceptive function across pain models. The left CeA has often been characterized to have no effect on pain modulation, a dampened pro-nociceptive function, or most recently an anti-nociceptive function. This review explores the current literature on CeA lateralization and the hemispheres' respective roles in the processing and modulation of different forms of pain.
Learn More >High-intensity training (HIT) improves rehabilitation outcomes such as functional disability and physical performance in several chronic disorders. Promising results were also found in chronic nonspecific low back pain (CNSLBP). However, the impact of different exercise modes on HIT effectiveness in CNSLBP remains unclear. Therefore, this study evaluated the effectiveness of various HIT exercise modes and compared differences between these modes, on pain intensity, disability, and physical performance, as a therapeutic intervention for persons with CNSLBP. In a randomized comparative trial, consisting of a 12-week program, persons with CNSLBP were divided into four HIT groups, i.e., cardiorespiratory interval training coupled with either general resistance training, core strength training, combined general resistance and core strength training, or mobility exercises. Before and after the program, the Numeric Pain Rating Scale (NPRS), Modified Oswestry Disability Index (MODI), and Patient Specific Functioning Scale (PSFS) were recorded, and a cardiopulmonary exercise test (VOmax, cycling time) and isometric trunk strength test (maximum muscle torque) were performed. Eighty participants (mean age: 44.0 y, 34 males) were included. Improvements were found within all groups after the HIT programs and ranged from -39 to -57% on the NPRS, +27 to +64% on the MODI, +38 to +89% on the PSFS, +7 to +14% on VOmax, and +11 to +18% on cycling time. No differences between groups were found. High-intensity cardiorespiratory interval training improves CNSLBP rehabilitation outcomes when performed with other HIT exercise modes or mobility exercises. Hence, when setting up an exercise therapy program in CNSLBP rehabilitation, various HIT modes can be considered as therapy modalities.
Learn More >(1) Background: Oxaliplatin is among the most neurotoxic anticancer drugs. Little data are available on the long-term prevalence and consequences of chemotherapy-induced peripheral neuropathy (CIPN), even though the third largest population of cancer survivors is made up of survivors of colorectal cancer. (2) Methods: A multicenter, cross-sectional study was conducted in 16 French centers to assess the prevalence of CIPN, as well as its consequences (neuropathic pain, anxiety, depression, and quality of life) in cancer survivors during the 5 years after the end of adjuvant oxaliplatin chemotherapy. (3) Results: Out of 406 patients, the prevalence of CIPN was 31.3% (95% confidence interval: 26.8-36.0). Little improvement in CIPN was found over the 5 years, and 36.5% of patients with CIPN also had neuropathic pain. CIPN was associated with anxiety, depression, and deterioration of quality of life. None of the patients with CIPN were treated with duloxetine (recommendation from American Society of Clinical Oncology), and only 3.2%, 1.6%, and 1.6% were treated with pregabalin, gabapentin, and amitriptyline, respectively. (4) Conclusions: Five years after the end of chemotherapy, a quarter of patients suffered from CIPN. The present study showed marked psychological distress and uncovered a failure in management in these patients.
Learn More >Virtual reality is a computer-generated environment that immerses the user in an interactive artificial world. This ability to distract from reality has been utilised for the purposes of providing pain relief from noxious stimuli. As technology rapidly matures, there is potential for anaesthetists and pain physicians to incorporate virtual reality devices as non-pharmacological therapy in a multimodal pain management strategy. This systematic narrative review evaluates clinical studies that used virtual reality in adult patients for management of acute and chronic pain. A literature search found 690 citations, out of which 18 studies satisfied the inclusion criteria. Studies were assessed for quality using the Jadad and Nottingham-Ottawa Scales. Agreement on scores between independent assessors was 0.87 (95%CI 0.73-0.94). Studies investigated virtual reality use: intra-operatively; for labour analgesia; for wound dressing changes; and in multiple chronic pain conditions. Twelve studies showed reduced pain scores in acute or chronic pain with virtual reality therapy, five studies showed no superiority to control treatment arms and in one study, the virtual reality exposure group had a worsening of acute pain scores. Studies were heterogeneous in: methods; patient population; and type of virtual reality used. These limitations suggest the evidence-base in adult patients is currently immature and more rigorous studies are required to validate the use of virtual reality as a non-pharmacological adjunct in multimodal pain management.
Learn More >Prodrugs (MRS7422, MRS7476) of highly selective A adenosine receptor (AR) agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2' and 3' hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known AAR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body AAR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked AAR agonists in models of two disease conditions.
Learn More >The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges.
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